Paper published in Tetrahedron Letters on phosphorothioate oligonucleotides

The phosphorothioate (PS) linkage has been widely utilized in oligonucleotide therapeutics.However, they are known to partially desulfurize during the cleavage and deprotection (C&D) step and could cause quality-control problems.

The purification of these impurities is quite difficult because they have physical properties similar to those of their intact counterparts.

Therefore, we developed a robust C&D method that suppresses the desulfurization of PS-modified oligonucleotides. As a result, we found that the desulfurization can be avoided by adding reducing inorganic salts to the reaction solutions.

Our method showed more effective inhibition of sulfur loss than the conventional method. In addition, this method also strongly reduced sulfur loss even under various severe conditions.

This new C&D method has potential application for manufacturing high-quality oligonucleotide drug substances.

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Tetrahedron Letters 133 (2023) 154843

Takaki Habuchi, Yuri Terao, Masayuki Utsugi

A robust method using reducing inorganic salts for preventing the desulfurization of phosphorothioate oligonucleotides during the cleavage and deprotection step

Tetrahedron Letters 133 (2023) 154843
DOI：10.1016/j.tetlet.2023.154843